Sphingosine-1 phosphate (S1P) is a bioactive sphingolipid that promotes
lymphocyte survival, cell migration, and inflammation. S1P agonism was
validated as a therapeutic approach in multiple sclerosis (MS) with the
approval of fingolimod (Novartis' Gilenya), a structural analogue of
S1P. Fingolimod, an oral non-specific S1P receptor family modulator
reduces relapse rates and disability progression in MS, but it has many
side effects. The drug has been successful as the first oral
disease-modifying drug (DMD) introduced into the MS armamentarium with
$1.03 billion in US and $1.9 billion in worldwide sales in 2013.

The S1P1 receptor subtype appears to drive fingolimod's clinical benefit
(via the inhibition of lymphocyte trafficking), while other receptor
subtypes mainly S1P3- account for most of its toxicities. Among safety
concerns, cardiac effects, macular edema, and melanoma rates have been
particularly concerning.

Next generation, selective S1P agonists or modulators are regarded as
promising strategies to improve risk/benefit over fingolimod treatment.

Receptos is developing RPC1063, pinning its hopes on the hypothesis that
a selective S1P1 receptor (S1P1R) agonist, RPC1063, will have activity
similar to fingolimod's but with better safety. Other oral, selective
S1P modulators in development are: